The long-term objective of the proposed research is to investigate clonal myeloid hemopathies, particularly Myelodysplastic Syndrome (MDS), and chronic myeloproliferative disorders (MPDs). With the resources of the Stanford-UCSF MDS Center, the goal is to improve the understanding of MDS and MPDs by coordinated clinical and laboratory research, and to evaluate novel therapies which are based on the biology of these disorders. One example of rational drug development is represented by the class of compounds termed farnesyltransferase inhibitors (FTIs). The proposed research will examine whether FTIs have activity in proliferative-type hematologic disorders in which de-regulation of the signaling protein Ras is implicated in their pathogenesis. FTIs target the post-translational modification of Ras, a critical step for its functional localization at the cytoplasmic plasma membrane surface. The FT1 R115777 (Janssen) is a potent inhibitor of Ras. Herein is proposed a phase 1/11 open-label, intrapatient clinical study for the use of R115777 in the treatment of adult patients with MPDs. The study will evaluate two MPD patient populations. One group will include patients who have received substantive prior treatment (e.g. interferon-resistant or intolerant CML). The second group will include patients with CMML, atypical CML, and undifferentiated MPDs (UMPDs), who have not received substantive prior treatment (e.g. generally only hydroxyurea). 25 patients, 12-13 in each group, will be recruited. Patients will be treated with R115777 for 21 days every 28 days for a total of 4 cycles. If no response is observed with 300 mg po bid after 2 cycles, the dose will be increased to 400 mg po bid for 2 more cycles. If greater than or equal to grade 3 non-hematological dose-limiting toxicity is observed at 300 mg po bid after 2 cycles, the dose will be decreased to 200 mg po bid. Primary endpoints will include evaluation of drug safety/toxicity and hematologic response. Secondary endpoints will include cytogenetic response, and biologic correlates such as N/K-ras mutation analysis and processing, MAP kinase activation, and in vitro CFU-GM cytotoxicity assays performed on patient bone marrows prior to study entry and at study completion. If clinically efficacious, further studies of R115777 in MPDs will be warranted.